Phenotypic and functional studies of the PD-1 molecule on CD4+ and CD8+ T cells performed on PBMC samples from uninfected and SIV infected rhesus macaques (RM) revealed 3 major findings: A) a rapid upregulation of PD-1 expression on tetramer positive CD8+ T cells from MamuA.01+ SIV infected macaques early post infection while upregulation of PD-1 on total CD8+ T cells was undetectable. B) In contrast, CD4+ T cells PD-1 expression was markedly higher in total CD4+ T cells during chronic infection and c) there was a correlation between the level of PD-1 expression on naive and central memory CD4+ T cells and the levels of viral loads. Such association was supported further by the finding of a marked decrease of PD-1 expression noted on tetramer positive CD8 T cells as well as on CD4+ T cells shortly after initiation of antiretroviral therapy and downregulation of viral replication in vivo. We have cloned rMamu PD-1 and fused it to a modified Rhesus IgG2 Fc molecule that is unable to bind complement or FcR on NK cells. SIV specific proliferation of CD8 but predominantly CD4 T cells from chronically infected monkeys was markedly amplified with the addition of such soluble PD-1 antagonist in a dose dependent manner. We therefore propose to use such a reagent to address the effect of PD-1-ligand blockade first in vitro on CD4 effectors and antigen specific CD8+ T cells as well as the relative role of PD-1 ligation on Treg cells and the potential DC subset most likely responsible for such signaling. In a second aim, blockade of the PD1-ligand interaction will be attempted during early and late chronic SIV infection in vivo to investigate whether such therapeutic attempts have the capability of restoring/enhancing anti-viral CD4 and CD8+ T cell effectors responses without inducing autoimmunity and prevent SIV mediated disease progression.